Bauer 2015
Bauer 2015
Bauer 2015
com/jdt
ISSN: 0954-6634 (print), 1471-1753 (electronic)
ORIGINAL ARTICLE
1
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria and 2FORIM GmbH, Mannheim, Germany
Abstract Keywords
Introduction: This study aims to explore the efficacy of the topical application of 10% Benzocaine, local anaesthetic,
benzocaine for treating pruritus and pain as compared to vehicle ointment. Methods: Twenty methaemoglobin, pain, pruritus,
male subjects were treated in a randomized double-blind fashion with the investigational
medicinal product (IMPD) and vehicle. Immediately after the injection of 100 mg histamine on History
both arms, subjects received topical treatment and pruritus was subsequently assessed with
visual analogue scale (VASpruritus) and Eppendorfer questionnaire. Ultraviolet B radiation (UVB) Received 15 August 2014
was administered on the back to induce slight sunburn. Twelve hours after UVB application Revised 10 October 2014
again the IMPD was applied on the right or left upper back and vehicle on the other side and Accepted 10 October 2014
Published online 11 February 2015
For personal use only.
pain related to sunburn was measured with VASpain and pressure algometry. Results: A trend
towards better reduction of pruritus was shown for benzocaine in VASpruritus. For the VASpain
significant differences in group comparison (p ¼ 0.02) were observed. Algometer measure-
ments showed onset of pain reduction in the verum group after 20 min whereas in the vehicle-
treated area pain relief occurred only after 60 min after application. Conclusions: The topically
administered ointment containing 10% benzocaine was found superior over vehicle for treating
pain, but not pruritus.
Introduction procedures. Several studies revealed the superior efficacy and fast
onset of action of benzocaine as anaesthetic agent to mucous
Local anaesthetics (LA) are often applied to relieve pain or
membranes when compared to e.g. lidocaine or to placebo (4–12).
itching sensations caused by various conditions. However, there is
Some other studies describe no significant differences in efficacy
a lack of scientific formally correct clinical studies to confirm vast
between benzocaine and the comparator topical anaesthetic
knowledge that has grown in less formal ways evaluating the
administered on mucous membranes, even though pain reduction
efficacy of these drugs (1). The procaine derivate benzocaine
has been observed (13–15). Other older studies investigating
(4-aminobenzoic acid ethyl ester; ethyl p-aminobenzoate) is a
topical application of benzocaine on the skin were not con-
member of the pharmacological class of LA. The cutaneous
ducted double-blind or vehicle-controlled, so they cannot prove
analgesic action of topical anaesthetics targets free nerve endings
efficacy. (16–18).
by preventing the initiation and transmission of nerve impulses
The tolerance of benzocaine is well-recognized based on a long
(2). This mechanism is achieved by limiting sodium ion
application history. Only weak side effects like minor headaches in
permeability by binding to a specific receptor site within the
individual people could be recognized. Methaemoglobinaemia
pore of the voltage-gated sodium channels and blocking ion
induced by benzocaine was occasionally reported as a possible side
movement through this pore. Benzocaine, perhaps because of its
effect when used as a topical oropharyngeal anaesthetic (19) and
small size and because of its lack of a tertiary amine component,
rarely after dermal application (20,21).
has been proposed to have separate binding sites from that of
Due to the lack of randomized, controlled studies, the present
traditional LA (3). The medicinal product ‘‘Anaestherit-10%’’
study set out to compare the activity of Anaestherit-10% in a
contains 10 g of the LA benzocaine in 100 g ointment which is
double-blind fashion to vehicle. For period one of the study a
approved for treating pain caused by burn wounds and sunburn.
histamine (pruritus) model and for period two an ultraviolet B
Benzocaine is frequently used for the local anaesthesia in the
radiation (UVB) (sunburn) model has been used. Pruritus is an
mouth to relieve pain caused by toothache, needle injection or for
unpleasant sensory perception of the skin associated with the
topical anaesthesia of mucous membranes before endoscopic
desire to scratch. Itch can be defined as a separate, pain-
independent sensation with its own mediators, spinal neurons and
cortical areas (22). Since many decades histamine has been used
Correspondence: Martin Bauer, Medical University of Vienna,
Department of Clinical Pharmacology, Waehringer-Guertel 18-20, 1090 as the pruritic stimulus in clinical studies (23–25). The onset of
Vienna, Austria. Tel: +43 1 40400 29810. E-mail: martin.m.bauer pruritus in histamine models is reported to be between 1 and
@meduniwien.ac.at 5 min after histamine application (26,27). The histamine model is
2 M. Bauer et al. J Dermatolog Treat, Early Online: 1–6
considered to be superior to the recently published administration were screened for study participation. Twenty subjects were
of cowhage (Mucuna pruriens) spicules on the superficial skin included in the study. They had a mean age ± standard deviation
e.g. as a model of itch due to insect bites (26). Pain related to of 25.2 ± 3.0 years (range, 20–30 years), mean body weight of
UVB-induced sunburn is an established, simple, acute pain model 76.0 ± 11.2 kg (range, 57.8–97.8 kg), and mean height of
(28,29). The measurement of pain under standardized conditions 183 ± 7 cm (range, 172–195 cm). For period 1, areas of 25 cm2
using an algometer was described earlier (30,31). were marked on each forearm; in the middle of these areas 100 mg
of histamine were injected intracutaneously at the same time for
Methods both arms. Immediately after histamine injection, 1 g of ointment
containing 10% benzocaine or 1 g vehicle ointment was applied
Ethics
on the respective forearm simultaneously in a randomized double-
This study is registered with EudraCT, number 2012 - 00283527. blind fashion. Each subject had to rate the intensity of pruritus
The study protocol, the informed consent form and the subject using VASpruritus at 1, 3, 6, 9, 12 and 30 min after application of
information sheet have been approved by the Ethics Committee of the ointment separately for both arms. The EIQ (1 b) was
Medical University of Vienna, Austria. The study was carried out performed immediately after VAS-rating separately for right and
in accordance with the Austrian drug law (AMG) and the rules of left forearm. The time-points have been chosen based on
Good Clinical Practice (GCP) as laid down in the European previously reported studies according to the expected peak
guideline on Good clinical practices (CPMP/ICH/135/95) in its efficacy of benzocaine and histamine (27,32). At the end of the
currently valid version. The clinical work was conducted in same study day, the MED was defined by UVB irradiation of
J Dermatolog Treat Downloaded from informahealthcare.com by University of Connecticut on 04/11/15
accordance with the ‘‘Declaration of Helsinki’’ (Seoul, Republic selected skin areas on the tight with a diameter of 2 cm each. The
of Korea, 2008). readout of UVB-light induced sunburn was carried out 24 h after
application of UVB. Thereafter a wash-out phase of 7–14 days in
Study drugs order to avoid carry over effects followed.
On the evening before the study day of period 2, subjects were
For the present study one batch of the vehicle ointment containing
confined at the study ward. They received UVB at their individual
white petrolatum, bis-diglyceryl polyacyladipate-2, polysorbate
MED on the right and left upper back (2 cm diameter). On the
80, medium chain triglycerides and myristyl myristate and one
following morning, 12 h after induction of sunburn, a baseline
batch of the investigational medicinal product (IMP) Anaestherit
VASpain as well as the measurement of painalgom was performed.
10%, containing additionally benzocaine, white petrolatum, bis-
Immediately after pain-rating, simultaneous application of either
diglyceryl polyacyladipate-2, polysorbate 80, medium chain
1 g investigational medication on the one site and vehicle on the
triglycerides and myristyl myristate, were used. Both were
other site was performed in a randomized and blinded way.
For personal use only.
Pressure algometry 49.70 ± 10.69 for the IMPD and 56.00 ± 11.41 for the
vehicle treatment. The mean results for VASpruritus are depicted
A hand-held pressure algometer (Wagner Force TenÔ FDX 50
in Figure 1 and the EIQ values are presented in Supplementary
Compact Digital Force Gage, Wagner Instruments, Greenwich,
Table 1.
CT) with a 1 cm2 flat circular rubber tip was used to quantify
For VASpain (Figure 2), statistically significant differences
deep-seated pressure pain in kilograms of force (kgf).
were observed between the groups (Wilcoxon matched pairs test
Subjects were instructed to tell the investigator as soon as they
p ¼ 0.013) and for time course (Friedman p ¼ 0.012). VASpain
experienced pain.
AUC values of both groups showed no statistically significant
Values outside mean value ± three sigma were predefined as
difference in the Wilcoxon matched pairs test comparison. The
outliers. Regarding algometer measurements, mean value ± three
mean VASpain AUC ± SE/cm*min values were 43.33 ± 5.93 for
sigma were 6.85 ± 8.72, therefore, values above 15.57 were
the benzocaine treatment and 71.89 ± 16.60 for vehicle.
excluded from all analysis. This resulted in exclusion of the value
Measurements of pain using the algometer FDX are depicted in
of algometer measurement at 1 h after treatment with investiga-
Figure 3. The mean painalgom AUC ± SE/kgf*min was
tional product from subject 18 and values at baseline and at time
2350.72 ± 136.79 for the IMPD and 2204.59 ± 114.25 for vehicle.
points 20 min, 1 h and 6 h after treatment with vehicle as well as
Comparisons between two groups including all time points
the 6 h value after treatment with vehicle for subject one.
resulted in no statistically significant difference in perception of
pressure-pain. However, statistically significant differences were
Determination of sample size
derived for the time course (Friedman p ¼ 0.026). The descriptive
J Dermatolog Treat Downloaded from informahealthcare.com by University of Connecticut on 04/11/15
The sample size calculation of this study was based on the results
of the controlled and randomized study published from Czepa
et al. (30). The primary power calculation was based on the
sunburn pain model. Therefore, the intensity of pain as estimated
applied force in Newton (1 kgf to 10 N) needed to induce pain was
used. A change in applied Newton of more than 10% was
considered clinically relevant. Taking into account these assump-
tions the sample size was determined as follows: An assumed
difference in experience of pain of 12 Newton (basic value
43 ± 17 Newton determined in the study named above) resulted in
a sample size of 18 subjects per group. We conducted the Power
Analysis with ¼ 20 % (0.80) and ¼ 0.05; according to a
For personal use only.
Statistical analysis
AUC for VAS (for pruritus and pain) and algometer measure-
ments were calculated with Microsoft Excel for Windows (version
2003, Microsoft, New York, NY). Figure 1. Time course of VAS score (0 to 10 cm) at period 1 after
Statistical analysis and descriptive statistics was performed by application of study drugs until 30 min following pruritus induction with
the STATISTICA software package for Windows (version 5, histamine (mean ± standard error (SE)). Full squares represent the values
StatSoft Inc., Tulsa, OK). According to the Shapiro–Wilk test, measured of the skin area with benzocaine application whereas open
values for pruritus and pain measurements of the IMPD and circles represent the values pain rating on site treated with vehicle
ointment.
vehicle group were not normally distributed. Therefore Wilcoxon
matched pairs test was calculated for comparisons of IMPD and
vehicle. The Friedman test was used to test for changes between
the single time points of the observed time period.
Results
Twenty subjects who received 10% benzocaine and vehicle
ointment after intracutaneously histamine challenge were ana-
lysed for efficacy and safety with regard to pruritus. One subject
did not get sufficient sunburn at the investigated UVB exposure
and dropped out from the study before period 2, therefore 19
subjects were included in the efficacy analysis for UVB induced
pain. The applied UVB dose, i.e. the individually assessed MED,
corresponded in all but one subject to a clinical erythema
assessment score of moderate redness of the skin. The individual
demographic data for each subject are listed in Supplementary
Table 1.
The results of the VASpruritus, VASpain and painalgom are shown
in Figures 1–3.
No significant differences for VASpruritus measurements were
Figure 2. Time course of VAS score (0–10 cm) at period 2 (pain model)
calculated for IMPD and vehicle for the single values (Wilcoxon after application of study drugs until 360 min (mean ± SE). Full squares
matched pairs test p50.437) and the time course (Friedman test represent the values measured of the skin area with benzocaine
p50.059). The mean area under the VASpruritus time- application whereas open circles represent the values pain rating on site
curve ± standard error of the mean (AUC ± SE/cm*min) was treated with vehicle ointment.
4 M. Bauer et al. J Dermatolog Treat, Early Online: 1–6
model) after application of study drugs until 360 min (mean ± SE). Full into account other aspects of pruritus, e.g. impact of pruritus on
squares represent the values measured of the skin area with benzocaine quality of life. Some subjects might also experience difficulties in
application whereas open circles represent the values pain rating on site
treated with vehicle ointment. translation of a ‘‘subjective symptom’’ into a point on a line.
Furthermore, individuals may rate their symptom in the VAS
when measured repeated with similar responses even though they
statistics of all assessments is presented in Supplementary report verbally significant changes in their pruritus. Therefore, the
Table 2. VAS may fail to detect some changes in pruritus severity (39). In
order to account for the subjective and multidimensional nature of
Safety assessment pruritus the EIQ as evaluation tool to these qualities has been
developed by Darsow et al. This validated questionnaire collects
The following adverse events were recorded in the course of the information about a subject’s subjective experience with pruritus
present study: palpitations (1), flushed skin after histamine using a detailed list of sensory and affective descriptor, but is
For personal use only.
administration (6), hot flash (2), skin rash (3) (all related to the limited in sensitivity to changes over time (34,39,40). In the
administration of histamine, not related to the study drug), present study no significant impact of treatment was observed for
injection site vasculitis (1) (related to the study procedure, not EIQ, which again might be attributed to the low level of
related to the study drug), rhinitis (2) and sore throat (2) (not sensations experienced (Supplementary Table 1).
related to study drug or study procedures). Additional to these, 14 In the course of the period 2 the subjects also rated their UVB-
subjects reported headache at period 1. All headaches did occur light induced sunburn pain intensity in general as low. VAS score
only at period 1 and not after the second application of study drug values ranging from 0 to 1.1 were reported for the sensation
at period 2. It might be assumed that this reaction was related to of spontaneous pain. It was therefore difficult to reveal signifi-
the application of histamine (CepleneÕ ), for which headache is a cant changes in pain when the IMPD and the vehicle were
very common and often reported adverse event/side effect (36,37). compared. Furthermore, a high inter-individual variability has
Sunburns were recorded as adverse events, however the induction been observed. Nevertheless, there was a statistically significant
of sunburns was part of the study protocol and therefore intended. difference in spontaneous pain underlining the superior efficacy
In addition, two cases of slight methaemoglobinaemia were in pain reduction of benzocaine as compared to vehicle ointment.
recorded during the present study. One case of methaemoglobin- Effect was observed through all time-points until 360 min
aemia was rated as possibly related to study drug because of the after application (Figure 2), however, maximum difference
close time dependency of the application of the study drug and between the two groups has been seen between 10 and 20 min
the occurrence of the adverse event. This criterion was missing in after application of the treatment, pointing out the time frame of
the other case. However, both subjects had a very low increase in maximum effect of benzocaine. During the subsequent time
methaemoglobin value (0.1%). Considering the raw data of these course the difference between the two groups becomes lower
subjects it needs to be stressed out that both entered the study with indicating that repeated administrations might become necessary
high baseline values (1.0% and 0.9%, respectively). Therefore, the for clinical treatment.
increase over the cut-off value for methaemoglobinaemia which is Additionally to the VAS rating as a subjective measure of
set at 4 1.0% was not considered to be clinically relevant. spontaneous pain perception, the algometer induced pain has been
used for measurement of anti-nociceptive treatment effects. While
the onset of pain reduction occurred in the benzocaine group after
Discussion
20 min, the vehicle treated area showed pain relief only after
Older studies investigating benzocaine ointments were not 60 min after application. After the first measurement of pain both
conducted in a blinded and controlled fashion and, despite treated sides of the subjects showed pain intensification. This
giving considerable signs supporting the suggested indications, might be due to the physiological development of sunburn up to
thereby cannot prove clinical efficacy according to modern 24 h after induction. An additional point to consider is the
standards of evidence based medicine. Therefore, the current physical irrigation of the sunburn area by the algometer, possibly
study was planned as double-blind, vehicle controlled clinical trial leading to higher perception of pain at subsequent measurements.
evaluating the efficacy of the benzocaine containing ointment for Nevertheless, it could be demonstrated that this pain intensifica-
treating pruritus and pain in two distinguished models. In the tion was less pronounced for the sunburn area treated with
present study, the clinical efficacy of benzocaine as pain relieving benzocaine, indicating prevention from pain aggravation due to
active ingredient was confirmed. physical irritation by the benzocaine containing ointment.
DOI: 10.3109/09546634.2014.992384 Benzocaine vs vehicle on pruritus and sunburn pain 5
In the US benzocaine has been an OTC since 1926 and has evaluation of the study, ILZ and KN did not personally receive payment
been found to be one of the safest topical anaesthetics available from the sponsor.
(11,41). In contrast to other LAs benzocaine is poorly water
soluble, therefore systemic absorption via the skin is low and
blood levels might be both sub-analgesic and insufficient to cause References
systemic adverse reactions (42).
In the present study no serious adverse events were observed. 1. Duque MI, Vogel CA, Fleischer Jr AB, Yosipovitch G. Over-the-
Flush and feeling of heat and sweat were attributed to histamine counter topical antipruritic agents are commonly recommended by
office-based physicians: an analysis of US practice patterns.
activity and are most probably not allergic type reactions or J Dermatol Treat. 2004;15:185–8.
reactions due to sensitization of the subjects to benzocaine. In 2. Hercogova J. Topical anti-itch therapy. Dermatol Ther. 2005;18:
addition two cases of slight methemoglobinaemia did occur in the 341–3.
present study. Both subjects had high baseline values (1.0% and 3. Wang GK, Quan C, Wang S. A common local anesthetic receptor for
0.9% respectively) and a very low increase in methaemoglobin benzocaine and etidocaine in voltage-gated mu1 Na+ channels.
value (0.1%), thus the observation was not considered clinically Pflugers Archiv: Eur J Physiol. 1998;435:293–302.
4. Graser GN. The efficacy of topical anesthetics in reducing intraoral
relevant. It is generally reported that clinical relevant symptoms
discomfort. Oral Surg Oral Med Oral Pathol. 1984;58:42–6.
due to methaemoglobinaemia occur at levels beginning from 5. Hersh EV, Cooper SA, Segal H, Greene J. Analgesic onset time as a
methaemoglobin levels of 10 - 20% and in rare cases led to measure of topical anesthetic efficacy in spontaneous toothache
cyanosis (43). In most cases the cyanosis is benign, but untreated,
J Dermatolog Treat Downloaded from informahealthcare.com by University of Connecticut on 04/11/15
25. Simone DA, Ngeow JY, Whitehouse J, et al. The magnitude and 37. Dr. Ritsert Pharma GmbH & Co KG. Summary of product
duration of itch produced by intracutaneous injections of histamine. characteristics ‘‘Anaestherit Salbe 10%’’. Eberbach, Germany: Dr.
Somatosens Res. 1987;5:81–92. Ritsert Pharma GmbH & Co KG, 2014.
26. Papoiu AD, Tey HL, Coghill RC, et al. Cowhage-induced itch as an 38. Darsow U, Ring J, Scharein E, Bromm B. Correlations between
experimental model for pruritus: a comparative study with hista- histamine-induced wheal, flare and itch. Arch Dermatol Res. 1996;
mine-induced itch. PLoS One. 2011;6:e17786. 288:436–41.
27. Theunis J, Black D, Degouy A, et al. Comparison of perceived itch 39. Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new
induced by skin prick-tests with histamine and codeine. Acta measure of pruritus. Br J Dermatol. 2010;162:587–93.
Dermato-Venereol. 2008;88:455–7. 40. Pfab F, Huss-Marp J, Gatti A, et al. Influence of acupuncture on type
28. Andresen T, Staahl C, Oksche A, et al. Effect of transdermal opioids I hypersensitivity itch and the wheal and flare response in adults
in experimentally induced superficial, deep and hyperalgesic pain. with atopic eczema – a blinded, randomized, placebo-controlled,
Br J Pharmacol. 2011;164:934–45. crossover trial. Allergy. 2010;65:903–10.
29. Rother M, Rother I. Placebo controlled, crossover validation study of 41. Spiller HA, Revolinski DH, Winter ML, et al. Multi-center
oral ibuprofen and topical hydrocortisone- 21-acetate for a model of retrospective evaluation of oral benzocaine exposure in children.
ultraviolet B radiation (UVR)-induced pain and inflammation. J Pain Vet Hum Toxicol. 2000;42:228–31.
Res. 2011;4:357–63. 42. PAZ_Arzeinmittel-Entwicklungs_GmbH. Systematische verfügbar-
30. Czepa D, Böttger MK, Stephan H, et al. Wirkung einer keit von benzocain nach topischer applikation. Frankfurt/M,
Kälteapplikation auf die Schmerzempfindlichkeit bei Patienten mit Germany: PAZ Arzneimittel-Entwicklungsgesellschaft mbH, 1992.
Hämophilie – Ergebnisse einer randomisiert kontrollierten Studie. 43. Tantisattamo E, Suwantarat N, Vierra JR, Evans SJ. Atypical
Conference Poster at the ‘‘42. Deutscher Sportärztekongress der presentations of methemoglobinemia from benzocaine spray. Hawaii
J Dermatolog Treat Downloaded from informahealthcare.com by University of Connecticut on 04/11/15
(Mucuna pruriens) and histamine. Acta Dermato-Venereol. 2009;89: TRPV1-mediated entry of impermeant sodium channel blockers.
271–7. Nature. 2007;449:607–10.
36. Dr. Ritsert Pharma GmbH & Co KG. Statistical evaluation of the 48. Roberson DP, Gudes S, Sprague JM, et al. Activity-dependent
Post Authorisation Safety Study conducted by Dr. Ritsert Pharma. silencing reveals functionally distinct itch-generating sensory
Eberbach, Germany: Dr. Ritsert Pharma GmbH & Co KG, 2010. neurons. Nat Neurosci. 2013;16:910–18.